1. Field of the Invention
This invention relates to improved processes for making (3S,4R)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-4-[1-oxo-3-thiolanylthio(t hiocarbonyl)thio]azetidin-2-ones of the formula ##STR1## which formula includes the racemic, cis- and optically active forms of the 4-position substituent of formula (I). It also relates to improvements in processes for making certain intermediates for formula (I) compounds and to a novel intermediate for formula (I) compounds.
Compounds of formula (I) are valuable intermediates for antibacterial 5R,6S-6-[1(R)-hydroxyethyl]-2-(1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids, formula (II), pharmaceutically-acceptable salts thereof and esters, especially the pivaloyloxymethyl esters, thereof: ##STR2## wherein said formula represents racemic, cis- and optically active forms of the 1-oxo-3-thiolanylthio moiety of (II).
2. Description of Related Art
Processes for the synthesis of penem compounds of formula (II) are described in U.S. Pat. Nos. 4,595,539 and 4,619,783. The first patent describes desulfurization of a xanthate or trithiocarbonate such as, for example, a p-nitrobenzyl-2-(4-alkylthio-2-oxo-1-azetidinyl)-2-[2-R.sub.1 thio(thiocarbonyl)thio]acetate (wherein R.sub.1 represents an organic moiety) followed by addition of an electrophilic reactant, e.g. acetyl chloride, to give the corresponding p-nitrobenzyl 2(4-alkylthio-2-oxo-1-azetidinyl)-3-acetylthio-3-(2-R.sub.1 -thioacrylate. The acrylate derivative is then converted to the corresponding 4-halo derivative by halogenation and then cyclized to give a penem.
The second patent, U.S. Pat. No. 4,619,783, describes the process comprising desulfurization of a xanthate or trithiocarbonate such as a p-nitrobenzyl 2-{4-alkylthio-3-[1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-1-azetidinyl }-2-(R.sub.1 oxythiocarbonylthio)acetate to the corresponding 2(R.sub.1 oxythiocarbonyl)acetate, followed by halogenation to the corresponding 4-halo derivative and cyclization to a 2-penem.
Each of the afore-mentioned patents also discloses conversion of 4-acetoxy-3-R-azetidin-2-ones (wherein R=H, 1-hydroxyalkyl or protected 1-hydroxyalkyl) to the corresponding 4-alkylthio-3-R-azetidin-2-ones by reaction with the sodium salt of the appropriate alkanethiol.
U.S. Pat. No. 4,619,924 describes reaction of 4-acetoxy-3[1(R)-(t-butyldimethylsilyloxy)ethyl]azetidin-2-one with sodium or potassium trithiocarbonates of the formula Na.sup.+ R.sub.1 --S--C(S)--S wherein R.sub.1 is an organic moiety to produce the corresponding 4-R-thio(thiocarbonyl)thioazetidin-2-one, e.g., of formula (I), and subsequent conversion of said azetidin-2-one to a compound of formula (II).
Compounds of formula (I) and (II) and their preparation from (3R,4R)-4-acetoxy-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]azetidin-2-one are described in U.S. Pat. No. 4,739,047.
Methods of preparing a number of (3S,4R)-3-[1(R)-hydroxyethyl]-4-(X-substituted)azetidin-2-ones of formula (III) ##STR3## which may bear a protecting group on the hydroxy group and/or nitrogen atom, and their use as intermediates, are reported in the literature. Representative of such compounds are the following:
______________________________________ X Reference ______________________________________ Alpegiani et al., Tetrahedron Lett. Cl 24, 1627 (1983). Endo, Can. J. Chem. 65, 2140 (1987). S-t-butyl Endo, Can. J. Chem. 65, 2140 (1987). OCOCH.sub.3 Leanza et al., Tetrahedron 39, 2505 (1983). OCOC.sub.6 H.sub.5 EP-181831, published May 21, 1986. COOC.sub.6 H.sub.5 COO(4-NO.sub.2 C.sub.6 H.sub.4) U.S. Pat. No. 4,614,614, issued SO.sub.2 (4-NO.sub.2 C.sub.6 H.sub.4 ) September 30, 1986. SO.sub.2 [2,4-(NO.sub.2).sub.2 C.sub.6 H.sub.3 ] SO.sub.2 CH.sub.3 Yoshida et al., Chem. Pharm. Bull. 29, 2899 (1981). Yoshida et al. (loc. cit.). Hirai et al., Tetrahedron Lett. 23, 4021, 1982. U.S. Pat. No. 4,614,614, issued September 30, 1986. SO.sub.2 C.sub.6 H.sub.5 Shiozaki et al., Tetrahedron Lett. 22, 5205 (1981). Shibasaki et al., J. Chem. Soc., Chem. Commun. 1324 (1982). Yanagisawa et al., Tetrahedron Lett. 24, 1037 (1983). S(C.sub.1-8 alkyl) U.S. Pat. No. 4,585,767, issued April 29, 1986. ______________________________________
A multistep synthesis of (3R,4R)-3-[1(R)-(t-butyldimethylsiloxy)ethyl]-4-methylsulfonylazetidin-2-o ne (formula III, X=SO.sub.2 CH.sub.3) from methyl (3S,5R,6S)-6-bromo-6[1(R)-hydroxyethyl]penicillanate is reported by Hirai et al., Tetrahedron Lett. 23, 4021 (1982). The synthesis involves tin hydride debromination of the starting material followed by protection of the hydroxy group of the 6-substituent by silylation with t-butyldimethylsilyl chloride and oxidation of the resulting product to the cis sulfone derivative. The crucial step of the synthesis, reported to be isomerization of the cis sulfone to the trans sulfone, was "satisfactorily" achieved by means of a catalytic amount of 1,5-diazabicyclo [4.3.0]non-5-ene (DBN) in methylene chloride at room temperature. Ring opening of the trans sulfone by treatment with excess methyl iodide and potassium t-butoxide afforded 3-[1(R)-(t-butyldimethylsiloxy)-ethyl]-4-methylsulfonylazetidin-2-one.
However, applicants have found that while DBN does achieve isomerization of the cis sulfone to the trans sulfone, as reported by Hirai et al. (loc. cit.), it fails to completely isomerize the protected hydroxyethyl group. Subsequent opening of the ring of the trans sulfone to afford the corresponding azetidinone in the Hirai et al. process by treating the sulfone with excess methyl iodide and potassium t-butoxide gave a mixture of isomers.
Japanese patent specification No. SHO 58-109490, published June 29, 1983, discloses that conversion of the 5,6-cis-compound of formula (IV) ##STR4## to the corresponding trans compound can be accomplished by treating the cis compound with any of a variety of organic bases such as DBN, DBU (1,8-diazabicyclo[5.4.0]-undec-7-ene, triethylamine and N,N-dimethylaniline. The disclosure notes the amount of base used can be a catalytic amount, but is usually 0.1 to 2 equivalents. However, it exemplifies the use of only DBN as isomerizing agent.
The synthesis of (III) wherein X is SO.sub.2 C.sub.6 H.sub.5 as described by Yanagisawa et al. (loc. cit.) involves, as one step, transformation of the epoxysulfone (V) to azetidin-2-one (III-A) in 82% yield ##STR5## by reaction with n-butyllithium (2-equivalents) in hexamethylphosphoric triamide (HMPT)-tetrahydrofuran at -50.degree. C. in an inert atmosphere. When the reaction was conducted in the absence of HMPT, the temperature had to be increased to room temperature. The product was a 3:1 mixture of (III-A) and its diastereomer.
U.S. Pat. No. 4,614,614 describes a process for converting (V) to (III-A) by treating (V) with a source of fluoride ion, e.g. tetra(n-butyl)ammonium fluoride in an aprotic solvent. Broad disclosure is presented to (3S) 3,4-trans disubstituted azetidin-2-ones wherein the 3-substituent is 1-hydroxyethyl or hydroxymethyl, optionally protected, and the 4-substituent is, inter alia, --SO.sub.2 R.sub.3 wherein R.sub.3 is an organic radical linked to the S atom by a carbon atom not bonded to hydrogen; or the 4-substituent is COOR.sub.3 ' wherein R.sub.e ' is an organic radical linked to the O atom of the carboxy group by a carbon atom not bonded to hydrogen. Representative examples of R.sub.3 and R.sub.3 ' are tert-lower alkyl, aryl, e.g. phenyl, or substituted aryl wherein the substituent is, for example, methoxy, methyl or nitro.
Shibasaki et al. (loc. cit.) report preparation of (III) wherein X is SO.sub.2 C.sub.6 H.sub.5 by oxidation of the corresponding compound wherein X is SC.sub.6 H.sub.5. A related oxidation procedure is described by Yoshida et al. (loc. cit.).
Shiozaki et al. (loc. cit.) report preparation of (III, X=SO.sub.2 C.sub.6 H.sub.5) by treatment of (III, X=OCOCH.sub.3) with two equivalents of sodium phenyl sulfonate in 63% yield.
Preparation of (III, X=C1) is disclosed by Alpegiani et al. (loc. cit.), the process comprising reaction of appropriate disulfides (III, X=-S-S-2-benzothiazolyl) with one molar equivalent of chlorine. It is described as being unstable to silica gel chromatography. Endo (loc. cit.) teaches its preparation by chlorinolysis of (III, X=t-butylsulfide) with two equivalents of chlorine. He discloses it "is rather unstable at room temperature but reasonably stable at -20.degree. C.," and notes its high reactivity at low temperatures relative to that of the acetoxy derivative (III, X=OCOCH.sub.3).
EP-181831 presents a broad disclosure of formula (III) compounds wherein X is --OCOR.sub.3 wherein R.sub.3 is lower alkyl, phenyl or substituted phenyl. The latter group is, for example, mono- to trisubstituted by groups such as lower alkoxy, lower alkyl and/or halogen.
U.S. Pat. No. 4,585,767 discloses preparation of 6-(1-hydroxyethyl)-2-aryloxy penems from 3-(1-hydroxyethyl)-4-substituted-azetidin-2-ones wherein the 4-substituent is a group capable of replacement by a nucleophilic group and is especially an acyloxy (e.g., acetoxy), sulphonyl (e.g., phenylsulphonyl) or halo (e.g., chloro).
Compounds related to those of formula (III) but in which the 3-position is unsubstituted or is substituted by one or two methyl groups and the 4-substituent is -YZ wherein Y is O, S or SO.sub.2 and Z is alkyl, phenyl, substituted phenyl, alkanoyl, benzoyl or substituted benzoyl are known from Clauss et al., Liebigs Ann. chem 539 (1974). The 4-acyloxy derivatives enumerated above serve as reactants for the other 4-substituted derivatives cited by nucleophilic displacement of the acyloxy group.
Procedures for preparing and for recovering (3S,4R)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-4-[1-oxo-3-thiolanylthio(t hiocarbonyl)thio]azetidin-2-ones (I) from reaction mixtures thereof are described in U.S. Pat. No. 4,739,047, issued Apr. 19, 1988 which exemplifies preparation of (3S,4R)-3-[1(R)-(t-butyldimethylsilyloxy)-ethyl]-4-[1(R)-oxo-3S-thiolanylt hio(thiocarbonyl)thio]-azetidin-2-one by reaction of (3R,4R)-4-acetoxy-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]azetidin-2-one with sodium 3S-(thio(thiocarbonyl)thio)thiolane 1(R)-oxide. The product was recovered by quenching the reaction with saturated ammonium chloride solution followed by extraction of the product with ethyl acetate and concentration of the dried extract. The crude product was purified by slurring it in isopropylether.
The above procedure involves aqueous steps which, while satisfactory for small scale reactions, are not suitable for large scale work-up due to poor stability of (I) under aqueous work-up procedures.